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1.
J Med Chem ; 63(9): 4655-4684, 2020 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-32118427

RESUMEN

A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 µM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 µM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.


Asunto(s)
Antineoplásicos/farmacología , Histona Acetiltransferasas/antagonistas & inhibidores , Hidrazinas/farmacología , Sulfonamidas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Descubrimiento de Drogas , Estabilidad de Medicamentos , Humanos , Hidrazinas/síntesis química , Hidrazinas/química , Hidrazinas/farmacocinética , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Estructura Molecular , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética
2.
J Med Chem ; 62(15): 7146-7159, 2019 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-31256587

RESUMEN

A high-throughput screen for inhibitors of the histone acetyltransferase, KAT6A, led to identification of an aryl sulfonohydrazide derivative (CTX-0124143) that inhibited KAT6A with an IC50 of 1.0 µM. Elaboration of the structure-activity relationship and medicinal chemistry optimization led to the discovery of WM-8014 (97), a highly potent inhibitor of KAT6A (IC50 = 0.008 µM). WM-8014 competes with acetyl-CoA (Ac-CoA), and X-ray crystallographic analysis demonstrated binding to the Ac-CoA binding site. Through inhibition of KAT6A activity, WM-8014 induces cellular senescence and represents a unique pharmacological tool.


Asunto(s)
Bencenosulfonatos/química , Descubrimiento de Drogas/métodos , Histona Acetiltransferasas/antagonistas & inhibidores , Histona Acetiltransferasas/metabolismo , Hidrazinas/química , Animales , Bencenosulfonatos/farmacología , Células CACO-2 , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Hidrazinas/farmacología , Ratones , Estructura Secundaria de Proteína
3.
Nature ; 560(7717): 253-257, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30069049

RESUMEN

Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function1. Among the genes coding for the MYST family of KATs (KAT5-KAT8) are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF)2,3. KAT6A has essential roles in normal haematopoietic stem cells4-6 and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia7,8. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers8. KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus9,10, a function that requires its KAT activity10. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days11. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.


Asunto(s)
Bencenosulfonatos/farmacología , Senescencia Celular/efectos de los fármacos , Histona Acetiltransferasas/antagonistas & inhibidores , Hidrazinas/farmacología , Linfoma/tratamiento farmacológico , Linfoma/patología , Sulfonamidas/farmacología , Acetilación/efectos de los fármacos , Animales , Bencenosulfonatos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Desarrollo de Medicamentos , Fibroblastos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Acetiltransferasas/deficiencia , Histona Acetiltransferasas/genética , Histonas/química , Histonas/metabolismo , Hidrazinas/uso terapéutico , Linfoma/enzimología , Linfoma/genética , Lisina/química , Lisina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Sulfonamidas/uso terapéutico
4.
Mol Microbiol ; 66(6): 1342-55, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18045383

RESUMEN

Staphylococcus aureus is a major pathogen that produces a family of 14 staphylococcal superantigen-like (SSL) proteins, which are structurally similar to superantigens but do not stimulate T cells. SSL11 is one member of the family that is found in all staphylococcal strains. Recombinant SSL11 bound to granulocytes and monocytes through a sialic acid-dependent mechanism and was rapidly internalized. SSL11 also bound to sialic acid-containing glycoproteins, such as the Fc receptor for IgA (FcalphaRI) and P-selectin glycoprotein ligand-1 (PSGL-1), and inhibited neutrophil attachment to a P-selectin-coated surface. Biosensor analysis of two SSL11 alleles binding to sialyl Lewis X [sLe(x)- Neu5Acalpha2-3Galbeta1-4(Fuc1-3)GlcNAc] coupled to bovine serum albumin gave dissociation constants of 0.7 and 7 mum respectively. Binding of SSL11 to a glycan array revealed specificity for glycans containing the trisaccharide sialyllactosamine (sLacNac - Neu5Acalpha2-3Galbeta1-4GlcNAc). A 1.6 A resolution crystal structure of SSL11 complexed with sLe(x) revealed a discrete binding site in the C-terminal beta-grasp domain, with predominant interactions with the sialic acid and galactose residues. A single amino acid mutation in the carbohydrate binding site abolished all SSL11 binding. Thus, SSL11 is a staphylococcal protein that targets myeloid cells by binding sialyllactosamine-containing glycoproteins.


Asunto(s)
Proteínas Bacterianas/química , Proteínas Recombinantes/química , Staphylococcus aureus/metabolismo , Superantígenos/química , Secuencia de Aminoácidos , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Western Blotting , Cristalografía por Rayos X/métodos , Citometría de Flujo , Granulocitos/metabolismo , Humanos , Inmunoglobulina A/metabolismo , Glicoproteínas de Membrana/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Monocitos/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Neutrófilos/microbiología , Selectina-P/metabolismo , Unión Proteica , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Receptores Fc/metabolismo , Proteínas Recombinantes/metabolismo , Homología de Secuencia de Aminoácido , Staphylococcus aureus/genética , Superantígenos/genética , Superantígenos/metabolismo , Resonancia por Plasmón de Superficie
5.
J Mol Biol ; 374(5): 1298-308, 2007 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-17996251

RESUMEN

Staphylococcus aureus is a significant human pathogen. Among its large repertoire of secreted toxins is a group of staphylococcal superantigen-like proteins (SSLs). These are homologous to superantigens but do not have the same activity. SSL5 is shown here to bind to human granulocytes and to the cell surface receptors for human IgA (Fc alphaRI) and P-selectin [P-selectin glycoprotein ligand-1 (PSGL-1)] in a sialic acid (Sia)-dependent manner. Co-crystallization of SSL5 with the tetrasaccharide sialyl Lewis X (sLe(X)), a key determinant of PSGL-1 binding to P-selectin, led to crystal structures of the SSL5-sLe(X) complex at resolutions of 1.65 and 2.75 A for crystals at two pH values. In both structures, sLe(X) bound to a specific site on the surface of the C-terminal domain of SSL5 in a conformation identical with that bound by P-selectin. Conservation of the key carbohydrate binding residues indicates that this ability to bind human glycans is shared by a substantial subgroup of the SSLs, including SSL2, SSL3, SSL4, SSL5, SSL6, and SSL11. This indicates that the ability to target human glycans is an important property of this group of toxins. Structural comparisons also showed that the Sia binding site in SSL5 contains a substructure that is shared by other Sia binding proteins from bacteria as well as viruses and represents a common binding motif.


Asunto(s)
Toxinas Bacterianas/química , Oligosacáridos/química , Staphylococcus aureus/química , Secuencia de Aminoácidos , Toxinas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Sitios de Unión , Cristalización , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Mutagénesis , Oligosacáridos/metabolismo , Conformación Proteica , Receptores de Superficie Celular/metabolismo , Homología de Secuencia de Aminoácido , Antígeno Sialil Lewis X
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